As Japan's population ages, there has been an increase in patients suffering from bone fractures, osteoporosis, articular rheumatism, lumbar pain and other bone diseases. The function of tissue in bone tissue is maintained by coordinating osteoblasts which support osteogenesis and osteoclasts which support bone resorption and by maintaining a balance between osteogenesis and hone resorption. The balance of bone metabolism is destroyed by aging, a decline in ovarian function as well as other factors. When osteogenesis decreases or when there is abnormal bone resorption the bone quantity (bone density) decreases and a variety of bone diseases occur. Bone diseases include bone fractures, bone deficiency, osteoporosis, osteomalacia, osteopenia, lumbar pain, Paget's disease of bone, tonic myelitis, articular rheumatism, deformative arthrosis and the like. In particular, when an elderly person is afflicted with a bone disease, it is difficult for that person to function on a level required for daily life and depending on the case, there is a risk that the patient will become bed-ridden. As a result, this is extremely significant in the prevention and treatment of bone diseases in modern society where an increasing number of people are elderly.
Activated vitamin D3, biphosphonate, calcitonin, hormone preparations containing estradiol, vitamin K2 preparations and the like are generally used as therapeutic agents for bone diseases. Estradiol derivatives, activated vitamin D3 derivatives, biphosphonate derivatives and the like are being developed as more effective therapeutic agents as they have fewer side effects (see Patent Document 1). However, vitamin D3 has an action which increases the concentration of calcium in the blood and estradiol and biphosphonate have a bone resorption inhibition effect. However, none of these has an effect which directly accelerates osteogenesis through the osteoblasts. A multiple drug therapy is the treatment of choice in this case so that there is a need to develop a novel preventive and therapeutic agent having a different action from that of the conventional preventive and therapeutic agents.
Bones are being recreated continuously in stages known as bone remodeling wherein the bone resorption stage and the following osteogenesis stage are repeated. The transition from one stage to another must be controlled precisely by secretion from the bone cell as it contributes to the communication between the osteoclast-osteoblast or by bone reconstruction factors released from the bone matrix. It is well known that TGF-β and IGF-1 released during bone resorption stimulate osteogenesis so that it is known, as a coupling factor. Although there is an abundance of in vitro data on candidate molecules which are extremely important for the coupling factor, there is still no in vitro evidence for this.
Axon guidance molecules manifest widely outside the nervous system. Therefore, cell wandering, the immune response, tissue development and angiogenesis and the like are controlled (see Non-Patent Documents 1 and 2). Based on research carried out in recent years, it is suggested that the axon guidance molecules of semaphorin and ephrin and the like contribute to intercellular communication between osteoclasts and osteoblasts (see Non-Patent Documents 3 through 5).
It is well known that Semaphorin 4D is secreted from oligodentrocytes and that it induces destruction of the growth cone in the central nervous system. It is also clear that semaphorin 4D is extremely important in maintaining the immune response and the homeostasis of the immune system. One well-known semaphorin 4D receptor is plexin-B1 (see Non-Patent Document 6). Furthermore, Non-Patent Document 7 suggests that osteoclast formation can be accelerated through the osteoblast differentiation inhibition action as well as the osteoblasts. Non-Patent Document 8 discloses that semaphorin 4D is not detected in the osteoblasts, that it is present on the surface of the osteoclasts and the bone quantity has been confirmed to increase as compared to wild-type mice in female sema4D-/- mice where Semaphorin 4D (Sema 4D) is deficient in homo [zygotes].